Gene therapy developers also need to keep an eye on demonstrating efficacy.

The recent decision in Europe to not recommend Amsterdam Molecular Therapeutics’ (AMT’s) gene therapy Glybera for approval could signal to other developers what to expect. While the science behind gene therapy and thus development efforts have come a long way, proving efficacy and navigating the regulatory pathway appear to remain roadblocks.

EMA’s Committee for Medicinal Products for Human Use (CHMP) voted on October 21 to maintain its earlier opinion of nonapprovability for Glybera (alipogene tiparvovec). AMT’s share price initially fell 69% on the news, dropping from €0.80 to a low of €0.25. The company subsequently decided to terminate further development of Glybera, saying a refiling would cost too much.

CEO Jorn Aldag told GEN that AMT had already invested €100 million in developing its adeno-associated viral (AAV) platform and Glybera. While AMT has cash until January 2012, “there is no way we can continue the development of Glybera at this point.”

Had Glybera received the green light, it would have become the first gene therapy approved outside of China. The only gene therapy currently on the market is Shenzhen SiBiono GeneTech’s Gendicine, which received the go-ahead from the Chinese State Food and Drug Administration in October 2003 for head and neck squamous cell carcinoma.

In 2009, AMT filed for European approval to market Glybera for the treatment of lipoprotein lipase (LPL) deficiency. Mutations in the LPL gene results in decreased or absent activity of LPL protein in patients, a protein required to break down large fat-carrying particles, chylomicrons, that circulate in the blood after each meal. As chylomicrons accumulate in the blood they may obstruct small blood vessels, which in turn can lead to pancreatitis. Glybera comprises an AAV derived vector used to deliver the LPL gene.

Regulatory Transparency Needed

The EMA’s ultimate rejection of Glybera occurred at the end of a long, uncertain regulatory path. AMT initially filed Glybera in December 2009. In May 2010, it received a list of questions from EMA. After two meetings with the agency, in July 2010, the company stated that it would not be required to conduct more clinical trials and in November 2010, submitted its response to the EMA’s questions.

The agency then sent another list of questions to AMT, but Aldag maintained that the company’s interactions with the EMA continued to be positive and that they were looking forward to a decision in mid-2011. That decision, unfortunately for AMT, was one of nonapprovability.

Aldag told GEN, “I remain in a bit of a fog because of the contradictions in the process. Two rapporteurs, the Scientific Advisory Group (SAG) invited by the Committee of Advanced Therapies (CAT), as well as the CAT itself, said Glybera should be approved under exceptional circumstances.

“It beats me why the CHMP would overrule the CAT, which was installed by the European Union at taxpayers’ expense to specifically review new therapies such as gene and stem cell therapies.”

One of the reasons CHMP cited for its decision was that too few patients were enrolled in the trial for sufficient long-term data to be established. But approval under exceptional circumstances may be granted if for reasons of the orphan or ultra-orphan nature of the disease there will never be sufficient patients for a controlled trial to give conclusive evidence of clinical benefit, Aldag explained.

“All these expert groups had concluded that there are early signs of clinical benefit to patients, but the CHMP took a different position.” SAG and CAT concluded that data from three Glybera clinical trials demonstrated meaningful evidence of clinical efficacy without any major safety concerns. CHMP, on the other hand, concluded that AMT’s studies had not shown a consistent long-lasting benefit of Glybera in terms of lowering blood fats in a clinically relevant manner and reducing the rate of pancreatitis.

In the wake of CHMP’s recommendation, AMT cut its workforce from 88 to about 50 employees. Aldag told analysts on October 25 during a call, “We have no more money to invest in a nontransparent process, and we have no idea how to gain European approval for Glybera.”

The company’s pipeline currently includes AAV-based gene therapy products for hemophilia B, DMD, acute intermittent porphyria, and Parkinson disease at different stages of R&D. Clinical trials are funded through a combination of private financing and academic institutions.

AMT expects to hold meetings with FDA and Canadian regulatory authorities in mid-November to obtain views on Glybera and gene therapy in general. If the regulatory agencies are positive about the drug, project funding will be sought to support filing of marketing authorizations in North America in the second half of 2012, Aldag told analysts in October.

Proving Efficacy

Glybera’s rejection is another in a long string of late-stage clinical trial or regulatory failures for gene therapies. In December 2009, CHMP rejected Ark Therapeutics’ malignant glioma treatment, Cerepro. According to EMA, Cerepro’s trial data was statistically underpowered and failed to show sufficient efficacy in terms of postponing death or re-intervention. Cerepro was the first gene therapy to be considered for approval by CHMP.

The decision sent Ark’s share price into a nosedive, as it dropped 43% to barely above the value of its cash assets; the company still hopes the EMA decision may be reversed on appeal. “The interpretation of the latest study was complicated by the changing standard of treatment for malignant glioma as the study was being carried out,” according to Ark.

Other notable gene therapeutic failures include Introgen’s Advexin for head and neck cancer and Li-Fraumeni syndrome. FDA refused its summer 2008 BLA, citing an incomplete application. Advexin was a replication-impaired adenviroal vector carrying the p53 gene. The Austin-based company filed for Chapter 11 bankruptcy protection in December 2008.

More recently, in March 2010, GenVec discontinued its Phase III trial of TNFerade™ in patients with locally advanced pancreatic cancer. The product was an adenovector that delivers the tumor necrosis factor alpha gene to cancer cells. After conducting an interim analysis of overall survival after the 184th death (two-third of total expected events) and consulting with its independent Data Safety Monitoring Board, the firm concluded that the trial would not meet the goal of demonstrating persuasive evidence of clinical effectiveness.

A common theme among discontinued or stalled gene therapy candidates in the recent past has been problems with demonstrating sufficient efficacy for these treatments, Aldag pointed out. “If you look at the regulatory process in Europe, there don’t seem to have been any gene-therapy specific risks mentioned.”

Pulling from his own experience, he explained that “specific risks usually associated with gene therapy, such as carcinogenicity, were not show stoppers with respect to Glybera and the adeno-associated viral vectors.” The company said that it has been able to design and validate a stable and scalable AAV production platform that can be applied to a large number of orphan diseases caused by one faulty gene.

Will Gene Therapy Deliver?

Aldag’s conclusion about factors impacting gene therapy development and approval was validated by Global Industry Analysts. It released a report last January stating that while safety concerns were once considered the major roadblock to successfully developing a gene therapy for market approval, efficacy is now the key challenge hindering quick entry of products onto the market.

The report went on to predict that the gene therapy market will reach $316 million by 2015 despite there being only one such product available, only in China. It suggested that demand for novel and efficient therapies to treat cancers and indications with high unmet needs will drive market growth.

Currently, however, the prospects for a gene therapy to gain approval in Europe or the U.S. does not seem to be close at hand. While researchers are continuously tweaking the science to improve efficacy of gene therapy candidates, another factor remains to be worked out: the pathway for getting a gene therapy approved and on the market.